Therapeutic modulation of the TP53 pathway. Strategies to activate p53 functions or p53-independent apoptotic pathways have been explored in p53-wt or p53-mut cancer cells. (1) Induction and activation of p53 by stress within the nucleus, including DNA damage caused by alkylating agents, DNA-intercalating agents, base analogs, irradiation, and ROS. Mitotic inhibitors and cell cycle-mediated drugs also effectively activate p53. (2) Therapeutic gene delivery of p53 and pharmacologic activation of p53 mutant. (3) Antagonism of MDM2-mediated degradation by MDM2 inhibitors and proteasome inhibitors. (4) Activation of the extrinsic apoptotic pathway by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TNF antibodies, or CFLAR/c-Flip inhibitors. (5) Enhancement of the intrinsic mitochondrial pathway of apoptosis by targeting Bcl-2 and IAP family members, or by directly activating caspases or BAX/BAK. (6) Induction of p53-independent apoptosis by various compounds and agents, mostly via the mitochondrial pathway and ROS generation. (7) Inhibition of survival pathways, including NF-κB, PI3K/Akt, and autophagy. (8) Induction of apoptosis by Cr(VI) through the calcium/Ca²⁺-calpain pathway and mitochondrial pathway induced by oxidative stress. (9) Increased unfolded/misfolded proteins that can be induced by proteasome inhibitors (Syrbactin, bortezomib), and increased intracellular Ca²⁺ concentration that can be induced by TG, can induce ER stress and autophagic cell death in several cancer cells.